The human platelet plasma membrane contains several hundred different proteins that control crucial functions,[unreadable] including adhesion to extracellular matrix, signal transduction, platelet aggregation, and clot retraction. Central to[unreadable] the ability of platelets to adhere to each other and to extracellular matrix is an abundant supply of cell surface[unreadable] adhesion molecules, including members of the integrin family, that exist in varying states of activation. These cell[unreadable] adhesion receptors, in turn, transmit signals into, and respond to signals from, the cell interior. The molecular[unreadable] details of the signaling pathways that regulate platelet activation and adhesion, however, remain incompletely[unreadable] understood. The goal of this project, therefore, is to examine four interrelated aspects of the molecular mechanisms[unreadable] underlying platelet activation and adhesion. Specific Aim 1 seeks to understand the molecular mechanism by[unreadable] which antibodies to platelet membrane glycoprotein (GP) VI result in the surgical removal of this important[unreadable] adhesion and signaling complex from the platelet surface, rendering platelets unresponsive to the extracellular[unreadable] matrix component, collagen, and less likely to participate in thrombus formation. It is hoped that these studies may[unreadable] enable rational design of future GPVI-specific therapeutics for the treatment of myocardial infarction and stroke.[unreadable] Specific Aim 2 proposes to test a recently-proposed and attractive hypothesis that specific amino acids within the[unreadable] membrane proximal beta-terminal domain of the integrin beta3 subunit control access of macromolecular ligands like[unreadable] fibrinogen and von Willebrand factor to ligand contact sites within the integrin head domain. These studies should[unreadable] provide important insights into how subtle allosteric changes within the extracellular domain might enable[unreadable] transformation of integrins from a low- to high-affinity state. Specific Aim 3 proposes to explore the hypothesis[unreadable] that PECAM-1 functions as an inhibitory receptor by sequestering the protein-tyrosine phosphatase, SHP-2, away[unreadable] from proteins that regulate the activation of Src family kinases. These studies will shed important new light on the[unreadable] mechanism by which PECAM-1, and perhaps other SHP-2 binding proteins, function to modulate cellular[unreadable] activation. Finally, Specific Aim 4 is a hypothesis-generating, translational research aim that seeks to determine[unreadable] whether PECAM-1 expression varies in the human population, and whether variable PECAM-1 expression might[unreadable] predispose individuals to arterial thrombosis or hemorrhage. These studies have the potential to add PECAM-1 to[unreadable] the growing list of cell adhesion and signaling receptors whose expression is linked to bleeding and clotting[unreadable] disorders in humans, and may thereby improve our ability to diagnose, treat, and prevent clinical thrombosis in[unreadable] humans. Together, these studies represent a coordinated line of investigation designed to advance our[unreadable] understanding of platelet physiology and lead to improvements in transfusion therapy, platelet storage, and[unreadable] management of platelet functional and immunological disorders.